title: Mechanism-based inactivation of CYP2C8 by gemfibrozil occurs rapidly in humans.
abstract: To study the time to onset of mechanism-based inactivation of cytochrome P450 (CYP) 2C8 by gemfibrozil in vivo, we conducted a randomized five-phase crossover study in 10 healthy volunteers. In one phase the volunteers ingested 0.25 mg of repaglinide alone (control), and in the other phases they received 600 mg of gemfibrozil 0-6 h prior to the repaglinide dose. When gemfibrozil was taken 0, 1, 3, or 6 h before repaglinide, the geometric mean ratio relative to control (90% confidence interval (CI)) of repaglinide area under the plasma concentration-time curve (AUC(0-∞)) was 5.0-fold (4.3-5.7-fold), 6.3-fold (5.4-7.5-fold), 6.6-fold (5.6-7.7-fold), and 5.4-fold (4.8-6.1-fold), respectively (P < 0.001 vs. control). The geometric mean ratio relative to control (90% CI) of the maximum plasma concentration (C(max)) of the CYP2C8-mediated metabolite M4 was 1.0-fold (0.8-1.3-fold), 0.10-fold (0.06-0.17-fold, P < 0.001), 0.06-fold (0.04-0.10-fold, P < 0.001), and 0.09-fold (0.05-0.14-fold, P < 0.001), respectively. The strong inactivation of CYP2C8, evident as soon as 1 h after gemfibrozil dosing, has implications in clinical practice and in studies with gemfibrozil as a CYP2C8 model inhibitor.
authors.affiliation: Department of Clinical Pharmacology, University of Helsinki, Helsinki, Finland.
authors.forename: J
authors.initials: J
authors.lastname: Honkalammi
authors.forename: M
authors.initials: M
authors.lastname: Niemi
authors.forename: P J
authors.initials: PJ
authors.lastname: Neuvonen
authors.forename: J T
authors.initials: JT
authors.lastname: Backman
mesh_terms: D000328:Adult; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002219:Carbamates / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D065727:Cytochrome P-450 CYP2C8; D005260:Female; D015248:Gemfibrozil / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology*; D005965:Glucuronates / Q000494:pharmacology; D006801:Humans; D007004:Hypoglycemic Agents / Q000493:pharmacokinetics*; D008297:Male; D010880:Piperidines / Q000493:pharmacokinetics*; D013997:Time Factors
chemical_list: D002219:Carbamates; D005965:Glucuronates; D007004:Hypoglycemic Agents; D010880:Piperidines; C072379:repaglinide; C094370:gemfibrozil 1-O-acylglucuronide; D001189:Aryl Hydrocarbon Hydroxylases; C450259:CYP2C8 protein, human; D065727:Cytochrome P-450 CYP2C8; D015248:Gemfibrozil